Certain-3-pyridine-sulfonamide derivatives

ABSTRACT

New 4-arylamino-3-pyridinesulfonic acids, e.g. those of the formula   THE N-oxide, esters and salts thereof, are diuretics.

United States Patent Mizzoni et al.

CERTAIN-3-PYlllDlNE-SULFONAMIDE DERIVATIVES Renat Herbert Mizzoni, LongValley; Herbert Morton Blatter, Summit, both of NJ.

Ciba-Geigy Corporation, Summit, NJ.

March 18,1970

Related 0.8. Application Data Continuation-impart of Ser. No. 876,038,Nov. 12, 1969.

inventors:

Assignee:

Filed:

App]. No.:

' References Cited ufifi'b STATES PATENTS Jucker et a]. ..260/294.8 F XJuly 4, 1972 Primary Examiner-Alan L. Rotman Attorney-Harry Goldsmith,Joseph G. Kolodny and Mario A. Monaco [57] ABSTRACT New4-arylamino-3-pyridinesulfonic acids, e.g. those of the formula R=H,alkyl, free, esterlfied or etherilied 011, Ch, N0 amino, free offunctionally converted carboxy or suifo R =H, alkyl or acyl the N-oxide,esters and salts thereof, are diuretics.

3 Claims, No Drawings CERTAIN-3-PYRIDINE-SULFONAMIDE DERIVATIVESCROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-partof application, Ser. No. 876,038,filed Nov. 12, 1969.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 4-arylamino-3-pyridinesulfonic acids andpharmaceutically useful acid or amino derivatives thereof, preferably ofthose corresponding to Formula I,

' these products. Said compositions are primarily useful as orallyapplicable diuretic, sodiand chloriuretic agents, in order to relieveexcessive water and/or salt retention, for example, in connection withheart or kidney diseases and in the adjunctive management ofhypertension.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The phenyl radical Ph isunsubstituted or substituted by one or more than one, preferably by upto three, advantageously one or two, of the same or differentsubstituents selected from the group consisting of lower alkyl, e.g.,methyl, ethyl, nor ipropyl or -butyl, free, etherified or esterifiedhydroxy, such as lower alkoxy, e.g., methoxy, ethoxy, nor i-propoxy or-butoxy, lower alkanoyloxy, e.g., acetoxy or propionyloxy, halogeno,e.g., fluoro, chloro or bromo, trifluoromethyl, nitro, amino, monoordi-lower alkylamino of lower alkyleneimino, e.g., monoor dimethylaminoor -ethylamino, pyrrodidino or piperidino, free, esterified or amidatedcarboxy or sulfo, e.g., lower carbalkoxy or alkoxysulfonyl, carbamoyl,sulfamoyl, monoor di-lower alkylcarbamoyl or -sulfamoyl, e.g.,carbomethoxy, carbethoxy, methoxysulfonyl, monoor dimethylcarbamoyl or-sulfamoyl. The term lower," referred to above and hereinafter inconnection with organic radicals or compounds respectively, defines suchwith up to seven, preferably up to four, carbon atoms.

Preferred Ph radicals are phenyl, monoor di-( lower alkyl)- phenyl,mono-, dior tri-(lower alkoxy)-phenyl, monoor di- (halogeno)-phenyl,(halogeno, lower alkyl)-phenyl, (halogeno, trifluoromethyl)-phenyl,monoor bis- (trifluoromethyl)-phenyl, (di-lower alkylamino)-phenyl,(carboxy )-phenyl, (lower carbalkoxy)-phenyl or (sulfamoyl)- phenyl.

The alkyl radicals R,, R, and R are preferably such with up to fourcarbon atoms, e.g., those mentioned above, especially methyl.

An acyl radical R, is preferably lower alkanoyl or alkenoyl, e.g.,acetyl, propionyl, pivaloyl, acryloyl or methacryloyl, or Ph-loweralkanoyl or -alkenoyl, e.g., benzoyl, phenylacetyl or cinnamoyl.

Esters of the acids of Formula I are preferably lower alkyl or hydroxy,lower alkoxy, amino or Ph)-lower alkyl esters, e.g., the methyl, ethyl,nor i-propyl, 2-(hydroxy, methoxy, amino or dimethylamino )-ethyl orbenzyl esters.

Salts of said acids are preferably those of therapeutically usefulinorganic or organic bases, primarily the alkali metal, alkaline earthmetal, e.g., sodium, potassium, magnesium or calcium salts, or ammoniumsalts from ammonia or amines,

such as those of mono-, dior tri-lower alkylamines, or tertiary nitrogenbases, such as pyridine, collidine or lutidine. Resulting compounds thatcontain basic groups, e.g., amino groups, may also form acid additionsalts, preferably such of therapeutically useful inorganic or organicacids, such as strong metalloidic acids, for example hydrohalic, e.g.,hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g., formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic,phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4aminosalicylic, embonic, nicotinic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic orsulfanilic acid; methionine, tryptophane, lysine or arginine.

The compounds of the invention exhibit valuable pharmacologicalproperties. Besides antiinflammatory effects, they primarily showdiuretic, natriand chloriuretic activity with rapid onset of action,high urine but low potassium excretion levels. This can be demonstratedin animal tests using, for example marnmals, e.g., rats or dogs, as testobjects. The compounds of the invention can be administered enterally orparenterally, for example orally within a gelatin capsule to dogs, or inthe fon'n of aqueous solutions or suspensions by stomach tube to rats.The oral dosage may range between about 0.1 and 50 mglkgjday, preferablybetween about 0.3 and 10 mg/kg/day, advantageously between about 1 and 5mg/kg/day. Simultaneously the test animals may receive vari' ous saltloads enterally or parenterally, for example, various amounts ofsubcataneously applied 0.9 percent saline, e.g., ml thereof permedium-sized dog (beagle). Thus, the compounds of the invention cause anincrease in the excretion of urine, which is collected, e.g., at 2 hourintervals, with or without catheterization, and its volume, sodium,potassium and chloride content estimated and compared with that of thesame untreated or saline-treated animals. Said compounds also cause inthe rat paw edema test [Winter et al, Proc. Soc. Exp. Biol. Med. lll,544 (1962)] a slight reduction of the paw edema induced by carrageenin.Accordingly, the compounds of the invention are mild antiphlogistics andpotent diuretics, sodiand chloriuretics, primarily useful in thetreatment or management of edematous water and salt retention, usuallyin connection with heart and kidney diseases or hypertension. They canalso be used as intermediates in the preparatioii of other valuableproducts, primarily of pharmacologically active compounds.

Preferred are those compounds of Formula I in which Ph is phenyl, monoordi-(lower alkyl)-phenyl, mono-, dior tri- (lower alkoxy)-phenyl, monoordi-(halogeno)-phenyl, (halogeno, trifluoromethyl)-phenyl, monoor bis-(trifluoromethyl)-phenyl, (dilower alkylamino)-phenyl, (carboxy)-phenylor (sulfamoyl)-phenyl, R, is hydrogen, lower alkyl or alkanoyl and eachof R and R is hydrogen or lower alkyl, as well as those compounds ofFormula I, wherein Ph also is (halogeno, lower alkyl)-phenyl or (lowercarbalkoxy phenyl and R -R have the meaning given in this paragraph, orthe lower alkyl esters, ammonium, alkali or alkaline earth metal saltsthereof.

Especially valuable are the compounds of Formula I in which Ph isphenyl, monoor dimethylphenyl, mono-, dior tri-methoxyphenyl, monoordichlorophenyl, (chloro. trifluoromethyl)-phenyl, mono orbistrifluoromethylphenyl. dimethylaminophenyl, carboxyphenyl orsulfamoylphenyl and each of R,, R and R is hydrogen, as well as suchcompounds of Formula I, wherein Ph also is monoor difluorophenyl.bromophenyl, (chloro, methyl)-phenyl or carbethoxyphenyl and each of R,and R are also methyl, or the sodium or potassium salt thereof.

The compounds of the invention are prepared according to methods inthemselves known. Advantageously they are obtained by converting in acompound of the Formula ll tional acid derivative different from thosedefined above, into the free acid, its esters or salts and, if desired,converting any resulting compound into another compound of theinvention.

The group X is, for example, a free or preferably reactively etherifiedor esterified hydroxy group, such as lower alkoxy, lower alkanoyloxy orhalogeno, e.g., such mentioned above, advantageously methoxy orchlorine, or above all a nitro group. Functional derivatives of the acidof Formula ll are, for example, the above-mentioned esters or theunsubstituted or N-alkylated amides or hydrazides.

The above-mentioned starting material is advantageously reacted with theamine R.,-Nl-l-Ph, wherein R is hydrogen or lower alkyl, preferably inthe absence, but also in the presence of diluents, advantageously ofthose which are inert to the reagents and are solvents thereof, ofcatalysts, condensing agents and/or inert atmospheres, at lowtemperatures, room temperature or advantageously elevated temperatures,at atmospheric or superatmospheric pressure.

In the above reaction the amine reagent is advantageously used inexcess, in order to neutralize any generated acid. It may, however, alsobe used in equivalent amounts and in the presence of other condensingagents such as inorganic or organic bases, e.g., alkali metal carbonatesor bicarbonates or tertiary nitrogen bases, for example tri-loweralkylamines, N,N-dimethyl-aniline or pyridine.

Any resulting amide or hydrazide can be hydrolyzed in the usual manner,for example, with the use of a base, e.g., an aqueous alkali or alkalineearth metal hydroxide, or a quaternary ammonium hydroxide. The compoundsof the invention so obtained may be converted into each other accordingto known methods. For example, resulting compounds in which R stands forhydrogen, may be reacted with a reactive ester of a correspondingalcohol, for example that of a hydrohalic or sulfonic acid or with areactive functional derivative of a corresponding acid, such as a halideor anhydn'de thereof, e.g., acetyl chloride or acetic anhydride.Resulting acyl derivatives or esters may be hydrolyzed, for example withthe use of acidic or alkaline hydrolyzing agents, esters transesterifiedor resulting acids esterified in known manner, i.e., either directlywith the use of lower alkanols and acidic catalysts, or indirectly viathe acid halides, which latter can be prepared with the use of thionylor phosphorus halides, e.g., thionyl chloride or phosphoruspentachloride. Resulting acids can also be salified in the usual manner,i.e., by reaction with corresponding inorganic or organic bases, e.g.,alkali metal or alkaline earth metal hydroxides, carbonates orbicarbonates, ammonia, amines or corresponding ion exchangepreparations. Resulting bases may also be converted into acid additionsalts by reacting them with the corresponding free acids or acidic ionexchange preparations.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances. Resulting mixtures ofisomers can be separated into the single isomers by methods inthemselves known, e.g., by fractional distillation, crystallizationand/or chromatography.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The starting material is known or, if new, may be prepared according tomethods illustrated in the examples herein. Compounds of Formula ll,wherein X is nitro, as well as the unsubstituted or N-alkylated amidesor hydrazides of the acids of Fonnula l, are new and are considered asadditional subject matter of the present invention. The former areprepared from the corresponding 4-aminopyridine-3-sulfonic acids ortheir functional derivatives, by oxidation, preferably with the use ofperoxides, such as hydrogen peroxide or advantageously persulfuric acid,which latter can be generated in situ from sulfuric acid and hydrogenperoxide. Said new sulfonamides or hydrazides exhibit also valuablephannacological properties, for example antiinflammatory effects. Theyare obtained according to the process described above, i.e., by choosingthe appropriate amides or hydrazides derived from the acids of Formulall.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharamaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine, (b) lubricants, e.g., silica, talcum. stearicacid, its magnesium or calcium salt and/or polyethyleneglycol, fortablets also (c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth. methylcellulose, sodiumcarboxymethylcellulose and/or polyvinyl-pyrrolidone, if desired, (d)disintegrants, e.g.. starches, agar, alginic acid or its sodium salt,enzymes of the binders or effervescent mixtures and/or (e) adsorbents,colorants, flavors and sweetners. lnjectable compositions are preferablyaqueous isotonic solutions or suspensions, and suppositories areadvantageously fatty emulsions or suspensions. They may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. They may also contain other therapeuticallyvaluable substances. Said pharmaceutical compositions are preparedaccording to conventional mixing, granulating or coating methodsrespectively and contain about 0.1 to 75 percent, preferably about I to50 percent of the active ingredient.

The following examples illustrating the invention are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade and all parts wherever given are parts by weight.

EXAMPLE 1 5 g 4-nitro-3-pyridinesulfonic acid are added portionwise to50 ml 3-chloroaniline while stirring and cooling, to keep thetemperature below 55. The mixture is stirred for 3 hours at undernitrogen, cooled and diluted with diethyl ether. The precipitate formedis filtered ofi', washed with diethyl ether and suspended in water. Thesuspension is neutralized with aqueous sodium hydroxide, filtered, thefiltrate evaporated in vacuo and the residu recrystallized from water,to yield the sodium 4-(3-chlorophenylamino)-3-pyridinesulfonate of theformula melting above 300 and showing in the thin-layer chromatogram onsilica gel using chloroform-methanol-diethylamine EXAMPLE 2 6 g4-nitro-3-pyridinesulfonic acid are added portionwise to 50 ml3-trifluoromethylaniline while stirring and cooling, to keep thetemperature below 55. The mixture is stirred for 3 hours at 100 undernitrogen, cooled and diluted with diethyl ether. The precipitate formedis filtered ofi" and recrystallized from ethanol, to yield the 4-(3-trifiuoromethylphenylarnino)- B-pyridinesulfonic acid of the formulaSOsH melting at 269270 with decomposition.

1 g thereof is taken up in the minimum amount of aqueous potassiumcarbonate, the solution washed with diethyl ether, evaporated in vacuoand the residue recrystallized from water, to yield the correspondingpotassium salt showing in the thinlayer chromatogram on silica gel,using chloroform-methanoldiethylamine (7:2: 1 an R 7.0.

EXAMPLE 3 7 g 4-nitro-3-pyridinesulfonic acid are added portionwise to70 ml 2-chloro-5-trifluoromethylaniline while stirring and cooling. Themixture is stirred under nitrogen at 120 for 4 hours, cooled and dilutedwith diethyl ether. The precipitate formed is filtered off andrecrystallized from methanol, to

yield the 4-(2-chloro-S-trifluoromethylphenylamino)-3- pyridinesulfonicacid of the formula G1 I 03H showing on silica gel inchloroform-methanol-diethylamine (8:2: 1) an R ,,,=8.0.

EXAMPLE 4 F30 SOQH showing on silica gel inchloroform-methanol-diethylamine (8:2:1 an Rf=9.0.

The starting material used in this and the previous examples is preparedas follows: To 216 ml 30 percent aqueous hydrogen peroxide, 432 mlconcentrated sulfuric acid are added at to 0 while stirring. Afterone-half hour, the solution of 60 g 4-amino-3-pyridinesulfonic acid in300 ml concentrated sulfuric acid are added dropwise while stirring at 5to +5. After stirring for 2 hours at 0", the mixture is allowed to standin a large water bath at room temperature for 16 hours. It is pouredonto 3 kg ice, filtered and the residue washed with water andisopropanol, to yield the 4-nitro-3- pyridinesulfonic acid melting at255255.5 with decomposition.

The mixture of 5 g 4-( S-trifluoromethylphenylamino)-3-( 3-trifluoromethylphenylsulfamoyl)-pyridine and ml 20 percent hydrochloricacid is refluxed for 2 hours and slowly evaporated. The residue iswashed with water and recrystallized from ethanol, to yield the4-(3-trifluoromethylphenylamino)-3-pyridinesulfonic acid melting at269270 with decomposition; it is identical with that obtained accordingto Example 2.

The starting material is prepared as follows: The mixture of 175.1 g4-hydroxy-3-pyridinesulfonic acid, 468 g phosphorus pentachloride and100 ml phosphorus oxychloride is refluxed for 6 hours while stirringunder nitrogen. It is evaporated in vacuo, the residue poured onto iceand the mixture extracted with methylene chloride. The extract is washedwith water, dried and evaporated. The residue is taken up in diethylether, the mixture filtered, the filtrate evaporated, the residuedistilled and the fraction boiling at l20-l22/l mm Hg collected, toyield the 4-chloro-3-pyridinesulfonyl chloride.

1 l g thereof are added portionwise to 100 ml 3- trifluoromethylanilinewhile cooling and the mixture stirred for 12 hours at under nitrogen. Itis cooled, filtered, the filtrate diluted with diethyl ether and theprecipitate formed triturated with diethyl ether. It is taken up inisopropanol. reprecipitated with diethyl ether, recrystallized from2-butanone-diethyl ether and chromatographed on silica gel usingbenzene-isopropanol (9:1) as the mobile phase. The slower movingfraction having R 5.5 is isolated, to yield the 4-( 3-trifluromethylphenylamino )-3-(3-trifluoromethylphenylsulfamoyl)-pyridine.

EXAMPLE 6 The mixture of 5 g 4-( 3-trifluoromethylphenylamino)-3-pyridinesulfonarnide and 100 ml 20 percent hydrochloric acid is refluxedfor 1 hour and slowly evaporated. The residue is washed with water andrecrystallized from ethanol, to yield the 4-(3-trifluoromethylphenylamino)-3-pyridinesulfonic acid melting at 269-270with decomposition; it is identical with the compound obtained accordingto Example 2.

The starting material is prepared as follows: The solution of 12 g4-chloro-3-pyridinesulfonyl chloride in the minimum amount of acetone iscooled to 5 and added dropwise to 20 ml concentrated aqueous ammoniawhile stirring at 58. After stirring for one-half hour at 0, it isfiltered, the residue washed with acetone and the filtrate againfiltered afier standing in the cold. The filtrate is evaporated invacuo, the residue recrystallized from isopropanol and ethanol-diethylether, to yield the 4-chloro-3-pyridinesulfonamide.

The mixture of 4 g thereof and 40 ml 3- trifluoromethylaniline isstirred for l2 hours at 150 under nitrogen. After cooling, it is dilutedwith diethyl ether, the precipitate formed filtered ofi andrecrystallized from isopropanol-diethyl ether, to yield the 4-( 3-trifluoromethylphenylamino)-3-pyridinesulfonamide hydrochloride. It istaken up in water, the solution neutralized with 10 percent aqueoussodium bicarbonate and evaporated in vacuo, to yield the correspondingfree base. The latter can be taken up in the minimum amount of ethanol,the solution neutralized with 2N sodium hydroxide, evaporated in vacuoand the residue recrystallized from ethanol, to yield the correspondingsodium salt having an R l 1.0 on silica gel usingchloroforrn-methanol-formic acid (45:45:10) as the mobile phase.

EXAMPLE 7 To 60 ml 3-chloroaniline, 15 g 4-nitro-3-pyridinesulfonic acidare added during 45 minutes while stirring and cooling with ice. Afterstirring overnight at room temperature, the mixture is trituratedseveral times with diethyl ethyl, the precipitate formed filtered offand washed with isopropanol and diethyl ether, to yield the4-(3-chlorophenylamino)-3- pyridinesulfonic acid of the formula 2 SOaHmelting at 283-285.

It is suspended in water, the suspension adjusted to pH 7.9 with 10percent aqueous sodium carbonate, the solution washed with diethyl etherand evaporated in vacuo. The residue is triturated with hot methanol,the solution filtered off and the filtrate evaporated in vacuo, to yieldthe corresponding sodium salt which is identical with that obtainedaccording to Example 1.

EXAMPLE 8 The mixture of methyl-4-nitro-3pyridinesulfonic acid and 50 ml3-trifluoromethylaniline is stirred for 2 hours at 1 10. After coolingit is diluted with diethyl ether, filtered and the residue washed withdiethyl ether, isopropanol and again diethyl ether, to yield the5-methyl-4-( 3-trifluoromethylphenylamino)-3-pyridinesulfonic acid ofthe formula melting above 320.

It is suspended in water, the pH of the suspension adjusted to 7.9 with10 percent aqueous sodium carbonate, the resulting solution washed withdiethyl ether and evaporated in vacuo. The residue is taken up in hotisopropanol, the solution filtered and the filtrate evaporated in vacuo,to yield the corresponding sodium salt melting at 3 l9-3 20.

The starting material is prepared as follows: To the mixture of 53.5 gconcentrated sulfuric acid and 13.4 g fuming sulfuric acid (containing20 percent sulfur trioxide), 25 g 4-amino-3- picoline are addedportionwise while stirring and keeping the temperature at 40-50. Themixture is heated to 195 for 20 hours under nitrogen, cooled andtriturated with diethyl ether until the washings become clear. The gummyresidue is further triturated with isopropanol until crystalline,filtered off and washed with hot isopropanol and diethyl ether, to yieldthe 4- amino-Smethyl-Lpyridinesulfonic acid, showing in the thinlayerchromatogram on silica gel, using methanol-water (9:1) as mobile phase,an R 10.0.

g thereof are taken up in 75 ml concentrated sulfuric acid and thesolution added dropwise to the mixture of 1 14 ml concentrated sulfuricacid and 57 ml 30 percent aqueous hydrogen peroxide while stirring at 5to +5". The mixture is stirred for half hour at 0 and 24 hours at 25. Itis poured onto ice, the precipitate formed filtered off, washed withwater, isopropanol and diethyl ether, to yield the 5-methyl-4-nitro-3-pyridinesulfonic acid melting at 268-269 with decomposition.

EXAMPLE 9 8.0 g 4nitm-Iipyridincsulfonic acid are added portionwise to45 ml ethyl 2-aminobenzoate while stirring under nitrogen,

whereupon the mixture is heated to for 2 hours. After cooling, it isdiluted with diethyl ether, filtered, the residue washed with hotisopropanol and diethyl ether, to yield the 4- (2-carbethoxypheny1amino)-3-pyridinesu1fonic acid.

The mixture of 10 g thereof and ml concentrated hydrochloric acid isheated on the steam bath for 2 hours, the precipitate formed filteredofi, suspended in water and the pH of the suspension adjusted to 8.1with 10 percent aqueous sodium carbonate. It is evaporated in vacuo, theresidue taken up in methanol, the solution filtered and concentrated, toyield the disodium 4-(2-carboxyphenylamino)-3-pyridinesulfonate of theformula showing on silica gel in chloroform-methanol-formic acid(7:2:1)anR ,,,=4.0.

EXAMPLE 10 According to the method illustrated by the previous examples,the following compounds of Formula 1 are prepared from equivalentamounts of the respective starting materials: R

All chromatograms on silica gel. A=chloroform-methanol-diethylamine(8:2:1 B chloroform-methanol-lonnic acid (9:1:1).

C methanol-water (9:1).

EXAMPLE 11 Preparation of 10,000 tablets each containing 50.0 mg of theactive ingredient:

Formula Sodium 4-(-chl0rophenylamino)- 3-pyridinesulfonate 500.00 gLactose 1,706.00 g Corn starch 90.00 g Polyethylene glycol 6,000 90.00 gTalcum powder 90.00 g Magnesium stearate 24.00 g Purified water q.s.

Procedure All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 45 ml water and the suspension added to theboiling solution of the polyethylene glycol in ml water. The pastefonned is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 7.1 mm diameter, uppers bisected.

We claim:

1. A 4-aryl-3-pyridinesulfonamide of the formula 10bis(trifluommethyl)-phenyl, di-(lower alkylamino)-phenyl R is hydrogen,lower alkyl or an acyl radical, each R R R R, or R is hydrogen or loweralkyl or a therapeutically useful acid addition salt thereof.

2. A compound as claimed in claim 1, in which formula Ph is phenyl,monoor dimethylphenyl, mono-, dior trimethoxyphenyl, monoordifluorophenyl, monoor dichlorophenyl, bromophenyl, (chloro, methyl)-phenyl, (chloro, trifluoromethyl)-phenyl, monoorbis-trifluoromethylphenyl, dimethylaminophenyl, and each of R R R and Ris hydrogen or methyl or a therapeutically useful acid addition saltthereof.

3. A compound as claimed in claim 1, and being the 4-( 34-(3-trifluoromethylphenylamino)-3-pyridinesulfonamide.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 7h79 Dated July '4, 1972 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 10, line 13, delete "(B- P" Signed and sealed this 6th day ofAugust 197t (SEAL) Attest:

. McCOY M. GIBSON, JR. C. MARSHALL DANN 'Attesting Officer Commissionerof Patents

2. A compound as claimed in claim 1, in which formula Ph is phenyl,mono- or dimethylphenyl, mono-, di- or trimethoxyphenyl, mono- ordifluorophenyl, mono- or dichlorophenyl, bromophenyl, (chloro,methyl)-phenyl, (chloro, trifluoromethyl)-phenyl, mono-orbis-trifluoromethylphenyl, dimethylaminophenyl, and each of R2, R3, R4and R5 is hydrogen or methyl or a therapeutically useful acid additionsalt thereof.
 3. A compound as claimed in claim 1, and being the4-(34-(3-trifluoromethylphenylamino)-3-pyridinesulfonamide.